NM_025114.4:c.5199A>G

Variant names:

• chr12-88080209-T-C
• rs79644671
• NM_025114.4:c.5199A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_025114.4(CEP290):​c.5199A>G​(p.Gln1733Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,610,522 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0068 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (13 hom.)
• Consequence: CEP290 NM_025114.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -1.21
• Publications: 1 publications found

Genes affected

CEP290 (HGNC:29021): (centrosomal protein 290) This gene encodes a protein with 13 putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Mutations in this gene have been associated with Joubert syndrome and nephronophthisis and the presence of antibodies against this protein is associated with several forms of cancer. [provided by RefSeq, Jul 2008]

CEP290 Gene-Disease associations (from GenCC):

• CEP290-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Bardet-Biedl syndrome 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Leber congenital amaurosis 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124902977 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-88080209-T-C is Benign according to our data. Variant chr12-88080209-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136730.
• BP7: Synonymous conserved (PhyloP=-1.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00682 (1039/152328) while in subpopulation AFR AF = 0.0241 (1000/41570). AF 95% confidence interval is 0.0228. There are 16 homozygotes in GnomAd4. There are 532 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025114.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	NM_025114.4	MANE Select	c.5199A>G	p.Gln1733Gln	synonymous	Exon 38 of 54	NP_079390.3	O15078

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.5199A>G	p.Gln1733Gln	synonymous	Exon 38 of 54	ENSP00000448012.1	O15078
	CEP290	ENST00000547691.8	TSL:1	c.2481A>G	p.Gln827Gln	synonymous	Exon 14 of 28	ENSP00000446905.3	A0A5K1VW81
	CEP290	ENST00000675476.1		c.6060A>G	p.Gln2020Gln	synonymous	Exon 40 of 56	ENSP00000502161.1	A0A6Q8PGB1

Frequencies

GnomAD3 genomes AF: 0.00683 AC: 1040 AN: 152210 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00184 AC: 447 AN: 243570 AF XY: 0.00138

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000683 AC: 996 AN: 1458194 Hom.: 13 Cov.: 31 AF XY: 0.000572 AC XY: 415 AN XY: 725094

African (AFR) AF: 0.0245 AC: 818 AN: 33366

American (AMR) AF: 0.00165 AC: 73 AN: 44240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1109964

Other (OTH) AF: 0.00133 AC: 80 AN: 60250

GnomAD4 genome AF: 0.00682 AC: 1039 AN: 152328 Hom.: 16 Cov.: 32 AF XY: 0.00714 AC XY: 532 AN XY: 74498

African (AFR) AF: 0.0241 AC: 1000 AN: 41570

American (AMR) AF: 0.00216 AC: 33 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00362 Hom.: 4

Bravo AF: 0.00767

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Bardet-Biedl syndrome 14 (1)
-	-	1	Joubert syndrome 5 (1)
-	1	-	Kidney disorder (1)
-	-	1	Leber congenital amaurosis (1)
-	-	1	Leber congenital amaurosis 10 (1)
-	-	1	Meckel syndrome, type 4 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome;C0687120:Nephronophthisis (1)
-	-	1	Senior-Loken syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.47
DANN	Benign	0.18
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs79644671; hg19: chr12-88473986;